Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P04637 (p53)
 77,613 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Inherited mutations of the p53 and neurofibromin genes are thought to cause two distinct neoplastic disorders in which gliomas occur, the Li-Fraumeni syndrome and neurofibromatosis type 1. We investigated the possibility that inherited mutations in specific regions of these genes also contributed to the clustering of gliomas in otherwise normal families. Twenty-six members of 16 families with glioma were screened for germline mutations of exons 5 through 9 of the p53 gene and exon 24 of the neurofibromin gene using a polymerase chain reaction-single-strand conformation polymorphism method. No germline mutations were found, suggesting that the genetic basis of familial glioma is distinct from that of gliomas occurring in the Li-Fraumeni syndrome, and that inherited mutations of the catalytic domain of neurofibromin do not predispose affected glioma families to these tumors.
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PMID:Absence of hereditary mutations in exons 5 through 9 of the p53 gene and exon 24 of the neurofibromin gene in families with glioma. 828 83

The identification of germ-line mutations in the p53 gene has provided a situation where comparable amounts of wild-type and mutant p53 co-exist in constitutional cells of certain individuals who are cancer-prone. Here we report the biochemical characteristics of several Li-Fraumeni syndrome associated mutant p53 proteins in order to assess the influence of germ-line mutant p53 on the functions of the wild-type p53. Unlike 248W mutant p53 protein, which was previously shown to have no effect on the wild-type p53 conformation (Milner & Medcalf, 1991; Cell 65, 765-774), germ-line associated mutant p53 proteins with residue 133T, 245D or 258K, converted the wild-type p53 conformation into the mutant conformation. Furthermore, lysates containing cotranslated wild-type p53 and these mutant p53 proteins were significantly impaired for DNA and SV40 large T antigen binding. These observations suggest that at least some germ-line p53 mutants might exhibit dominant effects on wild-type p53 functions and, like other mutant p53 proteins, the phenotype of germ-line mt p53 proteins might be variable depending on the particular mutation.
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PMID:Several mutant p53 proteins detected in cancer-prone families with Li-Fraumeni syndrome exhibit transdominant effects on the biochemical properties of the wild-type p53. 836 58

We describe molecular genetic findings in a patient who initially presented with an intermediate teratoma of the testis and who many years later presented with an oligodendro-astrocytoma. In addition he developed a malignant histiocytoma over the scapula, an adenocarcinoma of the stomach and a late stage adenoma of the sigmoid colon. Due to the development of several neoplasms the possibility of either ataxia telangiectasia or Li-Fraumeni syndrome was considered in differential diagnosis. A molecular genetic investigation revealed that both he and his brother carried a germline p53 tumor suppressor gene mutation at codon 248. From this result we conclude that this family belongs to the Li-Fraumeni syndrome. Once characterized as belonging to the Li-Fraumeni syndrome, the remaining members of the family were typed to determine if they too carried the same mutation. The two children of the index patient were shown not to carry the mutation and are therefore at no increased risk of developing any of the Li-Fraumeni spectrum of malignancies. A molecular genetic investigation into similar families could help to prevent the development of additional malignancies as seen in the index patient, as radiotherapy may interfere with the normal function of the p53 protein and this may in turn help to orchestrate DNA repair after radiation.
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PMID:[Hereditary p53 mutation in a patient with multiple tumors: significance for genetic counseling]. 839 84

We examined five patients with multiple primary cancers who had a history of three different types of primary cancers for germ-line p53 mutations. The germ-line p53 mutation was detected in a patient who conformed to the Li-Fraumeni syndrome, but not in the other four patients. The diagnosis of these four patients did not fall in the category of Li-Fraumeni syndrome. This result indicates that germ-line p53 mutations are uncommon even in patients with triple primary cancers.
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PMID:Germ-line p53 mutation is uncommon in patients with triple primary cancers. 840 98

Germline mutations in the tumor-suppressor p53 have been recently identified in Li-Fraumeni syndrome patients. We analysed the function of one of these mutations, an arg-to-trp substitution at amino acid 245 in the murine p53 gene. This p53LFS mutant could not, unlike wild-type p53, suppress foci formation of rat embryo-fibroblasts. Like other p53 mutants it cooperated with activated ras to transform rat embryo fibroblasts. Overexpression of p53LFS thus resulted in a phenotype similar to other mutant p53s. The p53LFS protein was also transcriptionally inactive in contrast to previous studies using a p53LFS/GAL4 fusion protein. To better understand the functional domain disrupted in p53LFS, we developed a dimerization assay and showed that p53LFS still dimerized. In addition, p53LFS retained its ability to bind SV40 large T antigen and not hsc70, both characteristics of wild-type p53. Using immunofluorescence, we localized p53LFS to the nucleus. From these results we conclude that p53LFS represents an unusual p53 mutant in that it retains many characteristics of wild-type p53, however activities critical for growth suppression are lost.
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PMID:A functionally inactive p53 Li-Fraumeni syndrome mutant. 842 39

The term "Turcot's syndrome" has been used to describe approximatively 55 patients with an association of colonic polyposis and primary neuroepithelial tumors of the central nervous system. The p53 tumor suppressor gene is a possible candidate underlying the syndrome because (a) mutations in the p53 gene are ubiquitous in human cancer, including colon carcinoma and gliomas, and (b) somatic or germ line mutations of the p53 tumor suppressor gene cause the Li-Fraumeni syndrome, which is characterized by the association of breast and soft tissue tumors. We determined the DNA sequence of the conserved regions of the p53 gene (exons 5 to 9) in the tumor tissues and lymphocytes of two patients with glioma-polyposis and found that mutations did occur as independent tumor-specific alterations but did not involve the germ line of these patients, suggesting that p53 may play a role in progression but not initiation of the disease.
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PMID:Turcot's syndrome of glioma and polyposis occurs in the absence of germ line mutations of exons 5 to 9 of the p53 gene. 843 70

Two genes predisposing females to autosomal dominant breast cancer are located on chromosome 17. Mutations in the p53-gene on the short arm have been shown to predispose females to early onset breast cancer in families with the rare Li-Fraumeni syndrome. Another locus on 17q (BRCA1), was found to be linked to the disease in a subset of families with breast cancer. In order to determine the involvement of tumour suppressor genes at these loci in tumour development, we studied allele losses for markers on chromosome 17 in 78 familial breast carcinomas. The analysis used six polymorphic DNA markers, three on each arm. We found support for at least four separate regions displaying allele losses on chromosome 17: the p53-region, the distal part of 17p, the BRCA1 region and the distal part of 17q. The frequency of allele losses on distal 17p (16%) is low in these familial tumours compared with the previously reported incidence in sporadic tumours (> 50%), whereas the frequency of losses at the p53 locus and on 17q was similar to sporadic tumours (5%-40%). These data suggest that several regions on chromosomal 17 can harbour tumour suppressor genes involved in tumour development of familial breast cancer.
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PMID:Four separate regions on chromosome 17 show loss of heterozygosity in familial breast carcinomas. 845 89

A novel germline p53 splicing mutation was identified in a pediatric patient with two metachronous primary cancers that are constituent tumors of the Li-Fraumeni syndrome. Genomic DNA from the second tumor showed the same mutation and loss of heterozygosity at the p53 locus. The mutant mRNA and protein were present in the tumor tissue. In contrast, in the normal tissues bearing the germline mutation in the heterozygous state, predominantly normal mRNA was expressed and the mutant p53 protein was not detectable. The functional silence and relative lack of mutant p53 mRNA expression in the normal tissues of this patient may be caused by decreased stability or decreased production. If this proves a more general pattern of expression of mutant p53 in individuals with germline mutations, these findings may explain the paucity of tumors in individuals affected with the Li-Fraumeni syndrome.
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PMID:A novel germline p53 splicing mutation in a pediatric patient with a second malignant neoplasm. 847 43

We report a constitutional mutation of codon 273 in exon 8 of the p53 gene. The affected individual has developed multiple independent benign and malignant tumours (tricholemmoma of the scalp, multiple trichoepitheliomata of the face, osteosarcoma of the ovary, bilateral breast cancer, malignant fibrous histiocytoma of the thigh and endometrial adenocarcinoma) and belongs to a family with some, but not all, features of the Li-Fraumeni syndrome. The mutation, found in both blood lymphocyte and tumour specimens, is a cytosine to thymine transition at codon 273, resulting in an amino acid change from arginine to cysteine. The mother and sister of the index case both died of tumours at an early age. We have demonstrated that formalin-preserved material from these tumours contains the same C-->T mutation at codon 273, indicating that this mutation has probably been transmitted through the germline. All tumours from the index case, both benign and malignant, showed immunohistochemical positivity with four antibodies to the p53 protein. Positive staining was also seen in scattered nuclei of morphologically normal epidermal keratinocytes and pilosebaceous cells, but not in lymphocytes or other morphologically normal cells from the index case. However, a similar staining pattern in apparently normal tissue was also observed in 13/48 sections from other individuals with various skin conditions (melanocytic naevi, psoriasis and normal skin adjacent to malignant melanoma and fibrous histiocytomas), suggesting that this pattern of p53 staining may not be unique to individuals with constitutional p53 mutations.
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PMID:Constitutional mutation in exon 8 of the p53 gene in a patient with multiple primary tumours: molecular and immunohistochemical findings. 847 49

Alterations of the TP53 tumor suppressor gene are present in various human malignancies and in the dominantly inherited Li-Fraumeni syndrome. Recently, a cell cycle checkpoint pathway involving p53 and GADD45 has been identified as defective in ataxia-telangiectasia. Using single strand conformation polymorphism analysis of PCR products, we looked for TP53 mutations in DNA of patients with AT. We did not find any mutation in 6 patients, suggesting that TP53 mutations are not directly involved in the cancer susceptibility observed in AT.
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PMID:Lack of mutations in the P53 gene exons 5 to 8 in ataxia-telangiectasia. 850 Jan 1


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